The human cellular homologs of several representative viral oncogenes including v-abl, v-fms and v-fes have been molecularly cloned by use of a cosmid vector system. Sequences representing the complete cellular homologs of these viral genes are dispersed over regions of from 12 to 40 kilobases (KB), are colinear with their viral counterparts, and contain variable numbers of intervening sequences. Sequences encoding the tyrosine phosphorylation acceptor region of the human c-abl oncogene have been identified, and by nucleic acid sequence analysis, shown to exhibit homology with acceptor regions of the v-src, v-yes, and v-fes/v-fps families of viral oncogenes. By somatic cell hybridization, c-fes has been localized to a region of human chromosome 15 that is translocated to chromosome 17 in acute promyelocytic leukemia, while c-fms has been mapped within the q24 band of chromosome 5. Using a similar approach, c-abl has been localized to the long (q) arm of chromosome 9. The further demonstration of the translocation of c-abl from chromosome 9 to chromosome 22 (the Philadelphia chromosome) in chronic myelogenous leukemia (CML) sublocalizes c-abl to the q34 terminal band of chromosome 9, establishes the Philadephia translocation to be reciprocal, and raises the possibility that c-abl may be involved in CML. These findings, in combination with recent studies in the c-myc system, raise the possibility that the association of chromosomal rearrangements with specific human cancers may involve a direct or indirect influence on expression of cellular oncogenes. In other studies, we have identified and molecularly cloned a new mammalian oncogene, v-raf, established the role of cytosine methylation in regulating viral and cellular oncogene expression, and identified a 150,000 Mr, highly phosphorylated cellular glycoprotein that specifically binds to, and is phosphorylated by, viral oncogene-encoded protein kinases. Finally, a transforming growth factor produced by Snyder-Theilen feline sarcoma virus (FeSV) transformed rat cells has been purified to homogeneity and its amino acid sequence determined.